tbuckley/cabot-search huggingface dataset:
P1441: SINGLE-CELL TRANSCRIPTOMIC CHARACTERIZATIONS OF BONE MARROW MONONUCLEAR CELLS AND CAR-T PRODUCTS ASSOCIATED WITH EFFICACY AND TOXICITY IN B-ALL PATIENTS
Authors: M. Du, C. Li, F. Zhou, W. Luo, Y. Zhang, L. Tang, J. Wu, H. Jiang, Q. Wei, C. Lu, H. Kou, H. Mei, Y. Hu
Journal: HemaSphere (2022)

Background: Chimeric antigen receptor-T (CAR-T) cell therapy has transformed B-cell acute lymphoblastic leukemia (B-ALL) treatment, yielding outstanding clinical results. However, less than half of patients achieve long-term remission, with treatment-associated adverse events a clinical challenge. Aims: This study aims to investigate the transcriptomic characterizations of CAR-T products and bone marrow mononuclear cells, and identify predictive biomarkers for efficacy and toxicity. Methods: Seventeen B-ALL patients were enrolled in this study. Single-cell RNA sequencing was performed on BMMCs (baseline and post-infusion) and IPs in 4 patients, and 120,780 residual cells were collected for bioinformatic analysis to identify biomarkers for the early clinical forecast. Another 13 patients-cohort was used for bulk RNA-sequencing validation. Results: An overview of our approach for sc-RNA-seq is shown in Figure A. Twenty-one distinctly transcriptional cell clusters were identified after extensive, unbiased clustering of all BMMCs and IPs (Figure B). Cell clusters were classified into five broad cell types -- IPs, HSPCs, NK/T cells, myeloid cells, and B-ALL cells (Figure C). For severe CRS prediction, 4 patients were divided into two groups based on tumor burden. Baseline cytokine-mediated signaling increased in high-tumor burden patients, mainly in B-ALL blasts, HSPCs (Pt 10 vs Pt 8); and low tumor burden patients, primarily in NK/T and Myeloid cells (Pt 11 vs Pt 9) (Figure D). IFITM1, a gene in IFN-related signaling pathways, was significantly upregulated in the above-mentioned cell types and validated in the bulk-RNA cohort (Figure E). Unlike complete response patients, NR (Pt 8) patients had diminished SRGN expression in every BMMC-1 cell type (Figure F), with probable arrests of IPs at the G1 phase (Figure G). In the NR patient tumor subsets, treatment-resistant tumor clusters (C1) in the IFN-I signaling pathway were enriched, whereas treatment-sensitive tumor cells (C3/5/10) underwent apoptosis (Figure H/I/J). Other ways, including the extracellular structure organization that predicts extramedullary relapse, were amplified (Figure K). The bulk RNA-sequencing cohort produced identical results. Image:Summary/Conclusion: IP and BMMC transcriptional feature heterogeneity possibly contributes to diverse clinical outcomes post-anti-CD19 CAR-T cell therapy and could be predictive.
Case 19-2022: A 29-Year-Old Woman with Jaundice and Chronic Diarrhea
Authors: Jon S. DuBois, Avinash Kambadakone, Jennifer Y. Wo, M. Lisa Zhang
Journal: New England Journal of Medicine (2022)

A 29-year-old woman was evaluated for a soft-tissue mass in the pancreatic head, discovered after diarrhea and jaundice occurred. Diagnostic procedures were performed, and management decisions were made.
P1486: TRIALS IN PROGRESS: THE THRIVE STUDIES EVALUATING THE EFFICACY, SAFETY, AND LONG-TERM TREATMENT WITH INCLACUMAB, A P-SELECTIN INHIBITOR, IN PATIENTS WITH SICKLE CELL DISEASE
Authors: B. Andemariam, A. Inati, R. Colombatti, C. Minniti, C. Brown, M. Hottmann, S. Gray, C. Hoppe, M. Davis, P. Yue
Journal: HemaSphere (2022)

Background: Sickle cell disease (SCD) is a group of autosomal recessive red blood cell (RBC) disorders caused by a single point mutation in the β-globin gene, resulting in the production of hemoglobin S. Hemoglobin S polymerization within deoxygenated RBCs contributes to hemolysis, vaso-occlusion, and end-organ damage. Abnormal heterocellular adhesive interactions between RBCs and endothelial cells, leukocytes, and platelets play a central role in triggering painful vaso-occlusive crises (VOCs) in patients with SCD. Inclacumab is a recombinant, fully human monoclonal antibody directed against human P-selectin, a cell adhesion molecule produced by endothelial cells and platelets. Inclacumab binding of P-selectin, and prevention of P-selectin ligand binding, interferes with the adhesion of sickle RBCs, platelets, and leukocytes to endothelium and is the putative mechanism by which inclacumab may potentially reduce the incidence of VOCs. Aims: We aim to conduct two global, multicenter, phase 3 studies and an open-label extension (OLE) study to evaluate the safety and efficacy of inclacumab in individuals with SCD. Methods: THRIVE-131 (NCT04935879) is a randomized, double-blind, placebo-controlled, multicenter trial in which ~240 participants aged ≥12 years experiencing 2 to 10 VOCs in the previous 12 months will be randomized 1:1 to receive intravenous (IV) inclacumab or placebo every 12 weeks for 48 weeks (Figure). The primary endpoint is the rate of VOCs during the 48-week treatment period. THRIVE-132 (NCT04927247) is a randomized, double-blind, placebo-controlled, multicenter trial in which ~280 participants aged ≥12 years experiencing 2 to 10 VOCs in the previous 12 months will be randomized 1:1 to receive a single dose of IV inclacumab or placebo within 5 days of resolution of an index VOC that required admission to a healthcare facility and treatment with parenteral pain medication. The primary endpoint is the proportion of patients with readmission for a VOC within 90 days of randomization. After completion of their participation in THRIVE-131 or THRIVE-132, participants may enroll in THRIVE-133 OLE, evaluating the long-term safety of inclacumab. In THRIVE-133 OLE, participants will receive IV inclacumab every 12 weeks as long as the clinical benefit of treatment outweighs the risk and until access to inclacumab from an alternative source (eg, through commercialization or a managed-access program) becomes available. Results: Recruiting for both THRIVE-131 and THRIVE-132 began in October 2021 and is ongoing. Image:Summary/Conclusion: The THRIVE-131 and THRIVE-132 phase 3 studies will examine the efficacy of inclacumab in reducing VOCs and readmissions due to VOCs, and the THRIVE-133 OLE study will examine the long-term safety of inclacumab in individuals with SCD.
Treating Man's Best Friend and Man Alike
Journal: Cancer Discovery (2022)

News in Depth| August 05 2022 Treating Man's Best Friend and Man Alike Author & Article Information Online ISSN: 2159-8290 Print ISSN: 2159-8274 ©2022 American Association for Cancer Research2022American Association for Cancer Research Cancer Discov (2022) 12 (8): 1831–1832. https://doi.org/10.1158/2159-8290.CD-ND2022-0010 Views Icon Views Article contents Figures & tables Video Audio Supplementary Data Peer Review Share Icon Share Facebook Twitter LinkedIn MailTo Tools Icon Tools Get Permissions Cite Icon Cite Search Site Article Versions Icon Versions Version of Record August 5 2022 Proof June 23 2022 Citation Treating Man's Best Friend and Man Alike. Cancer Discov 1 August 2022; 12 (8): 1831–1832. https://doi.org/10.1158/2159-8290.CD-ND2022-0010 Download citation file: Ris (Zotero) Reference Manager EasyBib Bookends Mendeley Papers EndNote RefWorks BibTex toolbar search Search Dropdown Menu toolbar search search input Search input auto suggest Search Advanced Search In the coming years, if the needle moves on standard care for osteosarcoma, and glioma's treatment landscape expands to include oncolytic viruses and molecularly targeted agents, dogs will deserve a big shout-out. “People don't typically see veterinarians as researchers, but as ‘the nice person who takes care of my sick pet,’” muses Amy LeBlanc, DVM, director of the NCI's Comparative Oncology Trials Consortium. “We're very much trained to think across species, though, and often encounter questions along these lines: ‘My dog got this cancer. How is it similar to or different than my grandfather's cancer?’” Such queries from savvy owners, who want the same treatment options for their pets that people have, are fueling the growth of comparative oncology. Other factors are also at play. “We now have tools to analyze dog tumors in ways we couldn't before, and there's a growing realization that current experimental models aren't optimal for... You do not currently have access to this content.
Error in Byline
Journal: JAMA Network Open (2022)

Asad H. Arastu, MD; Benjamin K. Elstrott, BA; Kylee L. Martens, MD; Jonathan L. Cohen, PharmD; Michael H. Oakes, MD; Zhoe T. Rub, MS; Joseph E. Aslan, PhD; Thomas G. DeLoughery, MD; Joseph Shatzel, MD
Outcomes Associated With Combination Shaving and Cryosurgery Treatment in Patients With Keloid Scars
Authors: Manon Artz, Alexandra Trimaille, Anne Labouche, Nathalie Kerfant, Laurent Misery, Weiguo Hu
Journal: JAMA Dermatology (2022)

This cohort study assesses whether shaving of the keloid scar followed by cryosurgery is associated with decreased scar volume.
Engineered Red Blood Cell Membrane‐Coating Salidroside/Indocyanine Green Nanovesicles for High‐Efficiency Hypoxic Targeting Phototherapy of Triple‐Negative Breast Cancer
Authors: Yi Pan, Yichen He, Xin Zhao, Yue Pan, Xuli Meng, Zhenye Lv, Zhiming Hu, Xiaozhou Mou, Yu Cai
Journal: Advanced Healthcare Materials (2022)

Triple-negative breast cancer (TNBC) presents special biological behavior and clinicopathological characteristics and leads to a worse prognosis than other types of breast cancer. The development of an effective therapeutic method is significant to improve the survival rate of TNBC cancer patients. In this work, an engineered red blood cell membrane (RBCm)-coating salidroside/indocyanine green nanovesicle (ARISP) is successfully prepared for hypoxic targeting phototherapy of TNBC. Salidroside in ARISP effectively ameliorates hypoxia-induced tumorigenesis by downregulating the expression of hypoxia-inducible factor 1α (HIF-1α), which increases the killing effect of reactive oxygen species on tumor cells during photodynamic therapy (PDT) using the photosensitizer indocyanine green. Besides, ARISP has an anti-LDLR modified RBCm-coating that extends its circulation time in the blood and escapes from immune surveillance and enhances hypoxia-targeted cellular uptake via the overexpressed LDLR receptor in hypoxic tumor sites. Moreover, guided by near-infrared fluorescence imaging and photoacoustic imaging, ARISP can eliminate tumors via high-efficiency phototherapy and inhibit lung and liver metastasis in TNBC models. Cytotoxicity assay of ARISP indicates the excellent biocompatibility with normal cells and tissues. This study provides fulfilling insights into the anticancer mechanism of reducing HIF-1α for enhanced PDT and has a promising therapeutic potential for TNBC treatment.
P1316: ASSESSING GENOMIC SAFETY OF ANTIVIRAL NUCLEOSIDE ANALOGS IN HEMATOPOIETIC STEM CELLS
Authors: F. Peci, J. de Kanter, N. Groenen, A. Rosendahl-Huber, L. Derks, E. Bertrums, S. Middelkamp, M. J. van Roosmalen, R. van Boxtel
Journal: HemaSphere (2022)

Background: Nucleoside analog (NAs) drugs are used for the treatment of a variety of diseases, such as cancers and viral infections. After phosphorylation of viral and host kinases, NA drugs compete with the corresponding naturally occurring nucleotide during DNA replication of the infected cell. After incorporation, they can lead to mutations, or chain termination. However, because of their mechanism of action, NA are also potentially mutagenic to the genome of physiologically normal cells. Indeed, we have shown that treatment with the antiviral NA ganciclovir (GCV) after stem cell transplantation induces an increased mutation burden in the hematopoietic stem and progenitor cells (HSPCs) of pediatric leukemia patients. Using mutational signature analysis, we provided evidence that GCV-induced mutagenesis contributes to development of relapses and second malignancies in pediatric patients by inducing driver mutations. Over 30 NA drugs have been approved for clinical use and millions of people receive antiviral treatment worldwide to treat viral infections, including COVID-19. However, the mutagenicity in normal cells and potential carcinogenicity is unclear. Aims: Here, we aimed to systematically assess the mutational consequences of antiviral NAs in human HSPCs and identify underlying mechanisms. Methods: By combining in vitro treatment of umbilical cord blood-derived HSPCs with whole-genome sequencing (WGS) analyses, we provide a compendium of mutational consequences of antiviral NAs in a relevant human tissue (i.e., toxicity to the hematopoietic system is often dose-limiting). We treated HSPCs with IC40-60 concentration of the assessed compound followed by clonal expansions to obtain sufficient DNA for WGS. Using established bioinformatic pipelines, we catalogued the somatic mutations and mutational signatures in these cells. Results: At time of writing, 5 out of 7 tested antiviral NAs induce an enhanced mutation burden in exposed HSPCs. For some of this antiviral NAs we were able to identify unique unreported mutational signatures. Of note, the thymidine analog brivudine showed the highest increase in single base substitutions, which were characterized by a T>C signature, depleted for flanking cytosines. Furthermore, like GCV, we also observed a signature characterized by C>ApA substitution after treatment with the penciclovir, a molecule nearly identical to GCV. Currently we are working on machine learning approach to identify relevant mutation characteristics and modes of action as well as to screen cancer genome databases for mutational signature occurrence. Summary/Conclusion: Many compounds of the NA class currently prescribed for the treatment of viral infections are mutagenic to healthy cells. This calls for more thorough screening of these drugs, incorporation of information on mutagenicity to healthy cells in drug safety guidelines and patient surveillance over time.
P773: THE ELEVATION OF RED BLOOD CELL DISTRIBUTION IS AN INDEPENDENT PROGNOSTIC FACTOR FOR JUVENILE MYELOMONOCYTIC LEUKEMIA
Authors: W. Liang, C. Liu, J. Zhang, M. Yi, Y. Cai, A. Zhang, L. Liu, L. Zhang, X. Chen, Y. Zou, Y. Chen, Y. Guo, Y. Zhang, X. Zhu, W. Yang
Journal: HemaSphere (2022)

Background: Juvenile myelomonocytic leukemia (JMML) is an overlapping myeloproliferative and myelodysplastic disorder of infants and early children. The existing clinical and laboratory prognostic features are inadequate to predict a worse outcome alone. New prognostic indicators are urgently needed since the great clinical heterogeneity. Red cell distribution width (RDW) is a parameter of the complete blood count (CBC) measured automatically by haematology analyzers to reflect the heterogeneity of erythrocyte size. In recent years, RDW has been suggested to have a high negative value for outcomes in various cancers. However, the role of RDW at diagnosis in patients with JMML is still unclear. Aims: Our aim is to investigate the prognostic role of RDW in children with JMML. Methods: We conducted a single center retrospective study to investigate the prognostic role of RDW in children with JMML. Seventy-seven patients were enrolled from January 1, 2008 to November 31, 2019. Survival rates were calculated and compared using Kaplan-Meier methods and log-rank tests. Univariate and Multivariate analysis was carried out according to the Cox proportional hazard regression model. Results: The mean red cell distribution width standard deviation (RDW-SD) for patients is 53.3(39.3-73.7) fl. Cox proportional hazard models showed that patients with RDW-SD >50.50fl at diagnosis were significantly associated with poor overall survival (OS) (HR = 5.22, CI = 1.50-18.21, P=0.010). The multivariate analysis demonstrated that the RDW-SD count was the independent risk factor for OS. Patients with PTPN11 mutation and RDW elevation displayed the worst survival rate, in comparison with other subgroups (P=0.00013). Summary/Conclusion: The results suggested that the elevated level of RDW is an independent prognostic factor for JMML. Furthermore, the PTPN11 mutation and a high RDW level may involve a synergy during the natural course of JMML.
P1247: GB5121 IS A NOVEL, IRREVERSIBLE, COVALENT BTK INHIBITOR WITH HIGH SELECTIVITY AND CNS-PENETRANCE FOR TREATMENT OF CNS MALIGNANCIES
Authors: I. Yusuf, D. Guimond, Z. Naiman, T. Schiff, B. Clemons, B. Paulson, K. Hou, K. Taylor Meadows, M. Rose, L. Carter
Journal: HemaSphere (2022)

Background: Inhibitors of Bruton’s tyrosine kinase (BTK) are approved treatments for several B cell lymphomas. However, they are characterized by modest selectivity and/or limited central nervous system (CNS) penetration. GB5121 is an orally available, selective, irreversible, covalent small molecule BTK inhibitor that was designed to address these limitations. Aims: To profile GB5121 for selectivity, potency, inactivation kinetics and CNS penetrance in comparison to ibrutinib. Methods: Selectivity of GB5121 and ibrutinib were assessed in kinome scans against 349 kinases at 1 µM compound concentration with 1mM ATP. Irreversible and covalent nature of GB5121 was evaluated using enzymatic assays compared to analogs that lacked an active covalent warhead. Both biochemical and cell-based assays were employed for evaluation of potency and inactivation kinetics of GB5121. For assessment of BTK target occupancy within the CNS, naïve mice with an intact blood brain barrier were dosed with either GB5121 or ibrutinib followed by perfusion, brain dissection and processing into lysates that were analyzed for unoccupied BTK in a probe-based ELISA assay. The pharmacokinetic profile of GB5121 was assessed in multiple species for both intravenous (IV) and oral routes of dosing. Results: In a kinome scan, GB5121 exhibited high kinase selectivity against 349 kinases with only TEC/TXK demonstrating >50% inhibition at 1 µM; additionally, GB5121 did not inhibit phosphorylation of EGFR in a cell-based assay. Importantly, GB5121 demonstrated rapid BTK inactivation kinetics (Kinact/Ki) in both peripheral and CNS tissues, a critical parameter for covalent irreversible inhibitors. When compared with ibrutinib, GB5121 showed superior CNS target occupancy in the brain of mice receiving three daily oral doses and demonstrated significantly higher brain to plasma ratio. In non-human primates, a 1:1 brain to plasma concentration ratio was demonstrated for GB5121 for up to 8 hours with both oral (30 mg/kg) and IV (2 mg/kg) doses. Summary/Conclusion: The unique profile of GB5121 provides differentiation from both FDA-approved BTK inhibitors and those currently under clinical investigation. Our data supports the use of GB5121 in clinical trials where BTK is a known driver of malignancies, including in CNS lymphoma. This research has been previously presented at the AACR Annual Meeting 2022.
Identification of Age-Associated Proteins and Functional Alterations in Human Retinal Pigment Epithelium
Authors: Xiuxiu Jin, Jingyang Liu, Weiping Wang, Jiangfeng Li, Guangming Liu, Ruiqi Qiu, Mingzhu Yang, Meng Liu, Lin Yang, Xiaofeng Du, Bo Lei
Journal: Genomics Proteomics & Bioinformatics (2022)

Retinal pigment epithelium (RPE) has essential functions, such as nourishing and supporting the neural retina, and is of vital importance in the pathogenesis of age-related retinal degeneration. However, the exact molecular changes of RPE during aging remain poorly understood. Here, we isolated human primary RPE (hRPE) cells from 18 eye donors distributed over a wide age range (10-67 years old). A quantitative proteomic analysis was performed to analyze changes in their intracellular and secreted proteins. Age-group related subtypes and age-associated proteins were revealed and potential age-associated mechanisms were validated in ARPE-19 and hRPE cells. The results of proteomic data analysis and verifications suggest that RNF123- and RNF149-related protein ubiquitination plays an important role in protecting hRPE cells from oxidative damage during aging. In older hRPE cells, apoptotic signaling-related pathways were up-regulated, and endoplasmic reticulum organization was down-regulated both in the intracellular and secreted proteomes. Our work paints a detailed molecular picture of hRPE cells during the aging process and provides new insights into the molecular characteristics of RPE during aging and under other related clinical retinal conditions.
P405: INHIBITION OF CKS1-DEPENDENT PROTEOSTASIS REVEALS VULNERABILITIES IN LEUKAEMIC STEM CELLS WITH CONCOMITANT PROTECTION OF HEALTHY HAEMATOPOIETIC STEM CELLS
Authors: W. Grey, A. Rio-Machin, P. Casado-Izquierdo, E. Gronroos, S. Ali, J. Miettinen, F. Bewicke-Copley, A. Parsons, C. Heckman, C. Swanton, P. Cutillas, J. Gribben, J. Fitzgibbon, D. Bonnet
Journal: HemaSphere (2022)

Background: Acute myeloid leukemia (AML) is an aggressive hematological disorder comprising a hierarchy of quiescent leukemic stem cells (LSCs) and proliferating blasts with limited self-renewal ability. AML has a dismal prognosis, with extremely low two-year survival rates in the poorest cytogenetic risk patients, primarily due to the failure of intensive chemotherapy protocols to deplete LSCs, and the significant toxicity towards healthy hematopoietic cells. Whilst much work has been done to identify genetic and epigenetic vulnerabilities in AML LSCs, little is known about protein homeostasis – so called “Proteostasis” – in drug resistance and relapse. Aims: - Characterisation of proteostatic targeting in AML and haematopoiesis. - Identify proteostatic vulnerabilities in LSCs. Methods: This study used a range of primary patient AML samples, highthroughput drug screening, in vivo transplantation models and proteomics to demonstrate mechanism of action and functionality of a small molecule inhibitor of CKS1-dependent protein degradation. Results: We tested a range of proteostatic targeting agents against primary, poor risk, AML patient samples and demonstrate a selective vulnerability of both AML blasts and LSCs to inhibition of CKS1-dependent protein degradation in vitro and in vivo using a small molecule inhibitor. Mechanistically, inhibition of CKS1 leads to hyperactivation of RAC1, increased NADPH production and critical levels of intracellular ROS, resulting in death of LSCs. Conversely, CKS1 inhibition has the opposite effect on healthy haematopoiesis. Healthy haematopoietic stem and progenitor cells (HSPCs) display increased quiescence upon inhibition of CKS1, a phenotype which confers chemoprotection of healthy HSPCs during clinical chemotherapy protocols (Cytarabine + Doxorubicin, 5 + 3). A phenotype conserved by intestinal stem and progenitor cells. Summary/Conclusion: Together these findings demonstrate a key vulnerability of AML-LSCs to CKS1-inhibition, while it preserves healthy stem cells. This offers the prospect of both depleting LSCs in vivo and bringing back clinically unfit patients into the pool for intensive chemotherapeutic treatment.